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Plasticity and Inflammation following Traumatic Brain Injury
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Traumatic Brain Injury (TBI) mainly affects young persons in traffic accidents and the elderly in fall accidents. Improvements in the clinical management have significantly improved the outcome following TBI but survivors still suffer from depression, memory problems, personality changes, epilepsy and fatigue. The initial injury starts a series of events that give rise to a secondary injury process and despite several clinical trials there is no drug available for clinical use that targets secondary brain injury mechanisms. Some recovery of function is seen during the first months following injury but is usually limited and there are no drugs that stimulate the recovery of lost function. Some of the recovery is attributed to plasticity, the brains ability to adapt to new circumstances, and enhancing plasticity via increased axonal growth has the potential to partly restore lost function. In this thesis mice were subjected to the controlled cortical impact model of TBI and functional outcome was evaluated using Morris water maze, the cylinder test and the rotarod. Brain tissue loss was measured in all Papers but the additional histological analyses differ among the Papers. Attempts to increase axonal growth were made by interfering with Nogo receptor function in Paper I and by conditional knockout of ephA4 in Paper II. Contrary to the hypothesis cognition was impaired in Paper I but otherwise no effects of treatment were detected in Paper I and II. Much is still unknown about plasticity and despite the discouraging results of Papers I and II this treatment approach is still worth further exploration. It is firmly established that TBI results in an inflammatory response and some aspects of it may damage brain tissue. In Papers III and IV the inflammatory response was attenuated using an IL-1β directed antibody which resulted in reduced tissue loss and edema while improving cognitive function. The results from Papers III and IV are encouraging and the possibility to find a treatment based on IL-1β inhibition appears promising.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2011. , 50 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 645
Keyword [en]
Traumatic Brain Injury, plasticity, inflammation, Nogo receptor, EphA4, IL-1β
National Category
Surgery
Research subject
Neuroscience
Identifiers
URN: urn:nbn:se:uu:diva-146551ISBN: 978-91-554-8008-0OAI: oai:DiVA.org:uu-146551DiVA: diva2:398436
Public defence
2011-04-01, Hedstrandsalen, Akademiska sjukhuset, ingång 70, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2011-03-10 Created: 2011-02-17 Last updated: 2011-05-04Bibliographically approved
List of papers
1. Genetic Deletion and Pharmacological Inhibition of Nogo-66 Receptor Impairs Cognitive Outcome after Traumatic Brain Injury in Mice
Open this publication in new window or tab >>Genetic Deletion and Pharmacological Inhibition of Nogo-66 Receptor Impairs Cognitive Outcome after Traumatic Brain Injury in Mice
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2010 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 27, no 7, 1297-1309 p.Article in journal (Refereed) Published
Abstract [en]

Functional recovery is markedly restricted following traumatic brain injury (TBI), partly due to myelin-associated inhibitors including Nogo-A, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp), that all bind to the Nogo-66 receptor-1 (NgR1). In previous studies, pharmacological neutralization of both Nogo-A and MAG improved outcome following TBI in the rat, and neutralization of NgR1 improved outcome following spinal cord injury and stroke in rodent models. However, the behavioral and histological effects of NgR1 inhibition have not previously been evaluated in TBI. We hypothesized that NgR1 negatively influences behavioral recovery following TBI, and evaluated NgR1(-/-) mice (NgR1(-/-) study) and, in a separate study, soluble NgR1 infused intracerebroventricularly immediately post-injury to neutralize NgR1 (sNgR1 study) following TBI in mice using a controlled cortical impact (CCI) injury model. In both studies, motor function, TBI-induced loss of tissue, and hippocampal beta-amyloid immunohistochemistry were not altered up to 5 weeks post-injury. Surprisingly, cognitive function (as evaluated with the Morris water maze at 4 weeks post-injury) was significantly impaired both in NgR1(-/-) mice and in mice treated with soluble NgR1. In the sNgR1 study, we evaluated hippocampal mossy fiber sprouting using the Timm stain and found it to be increased at 5 weeks following TBI. Neutralization of NgR1 significantly increased mossy fiber sprouting in sham-injured animals, but not in brain-injured animals. Our data suggest a complex role for myelin-associated inhibitors in the behavioral recovery process following TBI, and urge caution when inhibiting NgR1 in the early post-injury period.

Keyword
cognition, mossy fiber sprouting, NgR(-/-) mice, Nogo-66 receptor, traumatic brain injury
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-135948 (URN)10.1089/neu.2009.1255 (DOI)000280331100014 ()20486800 (PubMedID)
Available from: 2010-12-09 Created: 2010-12-09 Last updated: 2011-11-17Bibliographically approved
2. Functional and Histological Outcome following Focal Traumatic Brain Injury in Conditional EphA4-knockout mice
Open this publication in new window or tab >>Functional and Histological Outcome following Focal Traumatic Brain Injury in Conditional EphA4-knockout mice
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(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:uu:diva-145720 (URN)
Available from: 2011-02-10 Created: 2011-02-10 Last updated: 2011-05-04
3. Neutralization of interleukin-1β modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice
Open this publication in new window or tab >>Neutralization of interleukin-1β modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice
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2009 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 30, no 3, 385-396 p.Article in journal (Refereed) Published
Abstract [en]

Interleukin-1beta (IL-1beta) may play a central role in the inflammatory response following traumatic brain injury (TBI). We subjected 91 mice to controlled cortical impact (CCI) brain injury or sham injury. Beginning 5 min post-injury, the IL-1beta neutralizing antibody IgG2a/k (1.5 microg/mL) or control antibody was infused at a rate of 0.25 microL/h into the contralateral ventricle for up to 14 days using osmotic minipumps. Neutrophil and T-cell infiltration and microglial activation was evaluated at days 1-7 post-injury. Cognition was assessed using Morris water maze, and motor function using rotarod and cylinder tests. Lesion volume and hemispheric tissue loss were evaluated at 18 days post-injury. Using this treatment strategy, cortical and hippocampal tissue levels of IgG2a/k reached 50 ng/mL, sufficient to effectively inhibit IL-1betain vitro. IL-1beta neutralization attenuated the CCI-induced cortical and hippocampal microglial activation (P < 0.05 at post-injury days 3 and 7), and cortical infiltration of neutrophils (P < 0.05 at post-injury day 7). There was only a minimal cortical infiltration of activated T-cells, attenuated by IL-1beta neutralization (P < 0.05 at post-injury day 7). CCI induced a significant deficit in neurological motor and cognitive function, and caused a loss of hemispheric tissue (P < 0.05). In brain-injured animals, IL-1beta neutralizing treatment resulted in reduced lesion volume, hemispheric tissue loss and attenuated cognitive deficits (P < 0.05) without influencing neurological motor function. Our results indicate that IL-1beta is a central component in the post-injury inflammatory response that, in view of the observed positive neuroprotective and cognitive effects, may be a suitable pharmacological target for the treatment of TBI.

Place, publisher, year, edition, pages
Federation of European Neuroscience Societies and Blackwell Publishing Ltd, 2009
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-107781 (URN)10.1111/j.1460-9568.2009.06820.x (DOI)000268654900005 ()19614750 (PubMedID)
Available from: 2009-08-26 Created: 2009-08-26 Last updated: 2012-03-16Bibliographically approved
4. Neutralization of Interleukin-1β Reduces Cerebral Edema and Tissue loss and Improves Late Cognitive Outcome Following Traumatic Brain Injury in Mice
Open this publication in new window or tab >>Neutralization of Interleukin-1β Reduces Cerebral Edema and Tissue loss and Improves Late Cognitive Outcome Following Traumatic Brain Injury in Mice
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(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:uu:diva-145721 (URN)
Available from: 2011-02-10 Created: 2011-02-10 Last updated: 2011-05-04

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